Top

Inflammopharmacology

Published in:

01-04-2010 | Research Article

Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease

Authors: Lynn W. Maines, Leo R. Fitzpatrick, Cecelia L. Green, Yan Zhuang, Charles D. Smith

Published in: Inflammopharmacology | Issue 2/2010

Abstract

Aim

Activation of sphingosine kinase (SK) is a key response to many inflammatory processes. The present studies test the hypothesis that an orally available SK inhibitor, ABC294640, would be effective in rodent models of Crohn’s disease.

Methods

Trinitrobenzene sulfonic acid (TNBS) was administered rectally to mice and rats. Rats were treated with ABC294640 orally alone or in combination with olsalazine and disease progression was monitored.

Results

For both rodent species, treatment with ABC294640 attenuated disease progression. Colon samples from the ABC294640-treated animals had improved histology and cytokine parameters when compared with vehicle-treated animals. The expression of SK was similarly increased in TNBS-treated animals and in human colon tissue specimens from inflammatory bowel disease patients relative to normal, control patients.

Conclusions

Sphingosine kinase may be a critical mediator of colonic damage during intestinal inflammation, and pharmacologic inhibitors of this enzyme may prove useful in the treatment of Crohn’s disease.

Armstrong AM, Foulkes R et al (2001) Tumour necrosis factor inhibitors reduce the acute-phase response in hapten-induced colitis. Br J Surg 88(2):235–240CrossRefPubMed

Baumruker T, Bornancin F et al (2005) The role of sphingosine and ceramide kinases in inflammatory responses. Immunol Lett 96(2):175–185CrossRefPubMed

Canalis E, Pereira RC et al (2002) Effects of glucocorticoids on the skeleton. J Pediatr Endocrinol Metab 15(5):1341–1345PubMed

Chalfant CE, Spiegel S (2005) Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 118(Pt 20):4605–4612CrossRefPubMed

El Alwani M, Wu BX et al (2006) Bioactive sphingolipids in the modulation of the inflammatory response. Pharmacol Ther 112(1):171–183CrossRefPubMed

Fitzpatrick LR, Wang J et al (2000) In vitro and in vivo effects of gliotoxin, a fungal metabolite: efficacy against dextran sodium sulfate-induced colitis in rats. Dig Dis Sci 45(12):2327–2336CrossRefPubMed

Fitzpatrick LR, Small JS et al (2007) Enhanced intestinal expression of the proteasome subunit low molecular mass polypeptide 2 in patients with inflammatory bowel disease. Dis Colon Rectum 50(3):337–348CrossRefPubMed

French K, Zhuang Y et al. (2010) Pharmacology and Antitumor Activity of ABC294640, a selective inhibitor of sphingosine kinase-2. JPET. doi:10.1124/JPET.109.163444 (in press)

French KJ, Schrecengost RS et al (2003a) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63(18):5962–5969PubMed

French KJ, Schrecengost RS et al (2003b) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63(18):5962–5969PubMed

French KJ, Upson JJ et al (2006) Antitumor activity of sphingosine kinase inhibitors. J Pharm Exp Ther 318(2):596–603CrossRef

Itagaki K, Hauser CJ (2003) Sphingosine 1-phosphate, a diffusible calcium influx factor mediating store-operated calcium entry. J Biol Chem 278(30):27540–27547CrossRefPubMed

Kee TH, Vit P et al (2005) Sphingosine kinase signalling in immune cells. Clin Exp Pharmacol Physiol 32(3):153–161CrossRefPubMed

Kostin S, Pool L et al (2003) Myocytes die by multiple mechanisms in failing human hearts. Circ Res 92(7):715–724CrossRefPubMed

Leclercq TM, Pitson SM (2006) Cellular signalling by sphingosine kinase and sphingosine 1-phosphate. IUBMB Life 58(8):467–472CrossRefPubMed

MacKinnon AC, Buckley A et al (2002) Sphingosine kinase: a point of convergence in the action of diverse neutrophil priming agents. J Immunol 169(11):6394–6400PubMed

Maines LW, French KJ et al (2006) Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases. Invest Ophthalmol Vis Sci 47(11):5022–5031CrossRefPubMed

Maines LW, Fitzpatrick LR et al (2008) Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig Dis Sci 53(4):997–1012CrossRefPubMed

Mathias S, Dressler KA et al (1991) Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. Proc Natl Acad Sci USA 88(22):10009–10013CrossRefPubMed

McCafferty DM, Miampamba M et al (1999) Role of inducible nitric oxide synthase in trinitrobenzene sulphonic acid induced colitis in mice. Gut 45(6):864–873PubMed

Morris GP, Beck PL et al (1989) Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96(3):795–803PubMed

Murthy S, Flanigan A (1999) Animal models of inflammatory bowel disease. Birkhauser Verlag, Basel

Nakase H, Okazaki K et al (2001) An oral drug delivery system targeting immune-regulating cells ameliorates mucosal injury in trinitrobenzene sulfonic acid-induced colitis. J Pharmacol Exp Ther 297(3):1122–1128PubMed

Neurath MF, Fuss I et al (1997) Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice. Eur J Immunol 27(7):1743–1750CrossRefPubMed

Niwa M, Kozawa O et al (2000) Tumor necrosis factor-alpha-mediated signal transduction in human neutrophils: involvement of sphingomyelin metabolites in the priming effect of TNF-alpha on the fMLP-stimulated superoxide production. Life Sci 66(3):245–256CrossRefPubMed

Osawa Y, Banno Y et al (2001) TNF-alpha-induced sphingosine 1-phosphate inhibits apoptosis through a phosphatidylinositol 3-kinase/Akt pathway in human hepatocytes. J Immunol 167(1):173–180PubMed

Prieschl EE, Csonga R et al (1999) The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fc epsilon receptor I triggering. J Exp Med 190(1):1–8CrossRefPubMed

Rabano M, Pena A et al (2003) Sphingosine-1-phosphate stimulates cortisol secretion. FEBS Lett 535(1–3):101–105CrossRefPubMed

Sandborn WJ, Feagan BG et al (2007) Medical management of mild to moderate Crohn’s disease: evidence-based treatment algorithms for induction and maintenance of remission. Aliment Pharmacol Ther 26(7):987–1003PubMedCrossRef

Smith CD, French KJ et al. (2008) Sphingosine kinase inhibitors. US, Apogee Biotechnology Corporation, US 7,338,961 B2

Stasi MA, Ruggiero V et al (2004) Ameliorating effects of the immunomodulator 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H–1, 2, 4-triazole in an experimental model of colitis in the rat. Eur J Pharmacol 494(2–3):263–272CrossRefPubMed

Taha TA, Hannun YA et al (2006) Sphingosine kinase: biochemical and cellular regulation and role in disease. J Biochem Mol Biol 39(2):113–131PubMed

Videla S, Vilaseca J et al (2006) Selective inhibition of phosphodiesterase-4 ameliorates chronic colitis and prevents intestinal fibrosis. J Pharmacol Exp Ther 316(2):940–945CrossRefPubMed

Williams KL, Fuller CR et al (2001) Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone. Gastroenterology 120(4):925–937CrossRefPubMed

Xia P, Gamble JR et al (1998) Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proc Natl Acad Sci USA 95(24):14196–14201CrossRefPubMed

Xia P, Wang L et al (1999) Activation of sphingosine kinase by tumor necrosis factor-alpha inhibits apoptosis in human endothelial cells. J Biol Chem 274(48):34499–34505CrossRefPubMed

Yamanaka M, Shegogue D et al (2004) Sphingosine kinase 1 (SPHK1) is induced by transforming growth factor-beta and mediates TIMP-1 up-regulation. J Biol Chem 279(52):53994–54001CrossRefPubMed

Yatomi Y, Ruan F et al (1995) Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood 86(1):193–202PubMed

Zhang M, Deng C et al (2006) Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma. Int Immunopharmacol 6(8):1233–1242CrossRefPubMed

Title: Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease
Authors: Lynn W. Maines
Leo R. Fitzpatrick
Cecelia L. Green
Yan Zhuang
Charles D. Smith
Publication date: 01-04-2010
Publisher: SP Birkhäuser Verlag Basel
Published in: Inflammopharmacology / Issue 2/2010
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-010-0032-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease

Abstract

Aim

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aim

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2010

Erratum to: FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?

FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?

Relevance of Helicobacter pylori genotypes in gastric pathology and its association with plasma malondialdehyde and nitric oxide levels

Synergism between COX-3 inhibitors in two animal models of pain

Hepatoprotective effects of the nitric oxide donor isosorbide-5-mononitrate alone and in combination with the natural hepatoprotectant, silymarin, on carbon tetrachloride-induced hepatic injury in rats

Hungarian Experimental and Clinical Pharmacology Society Abstracts